Multiple sclerosis (MS) is a debilitating neurodegenerative disease affecting greater than 300,000 Americans. The annual cost of MS. is in excess of 52.5 billion and the cost in terms of human suffering is immeasurable. Current treatments are few, and due to serious side -effects, their use is limited. There exists no cure for MS. Gelatinase-B also known as matrix metalloproteinase 9 (MMP-9), has been implicated in the pathogenesis of MS. Its secretion by lymphocytes is believed to be necessary for invasion and-breakdown of the blood brain barrier. Although broad spectrum inhibitors of all MMPs help to ameliorate the symptoms. they also produce severe side effects. Here we propose to develop anti-MMP-9 antisense therapeutics for the treatment of MS. The high specificity of these agents is expected to result in few or no side effects. Suitable targets for anti-MMP-9 antisense therapeutics will be identified and verified as outlined in specific aims l through 3. These studies will lead to the development of potent MS therapeutics in Phase II. l. Produce anti-MMP-9 antisense RNA and ribozyme libraries. 2. Use the libraries to identify effective anti~MMP-9 antisense RNA or ribozymes. 3. Verify the activity of effective antisense molecules by zymography. PROPOSED COMMERCIAL APPLICATIONS: Multiple sclerosis afflicts greater than 350,000 Americans at a cost in excess of $2.5 billion annually. The cost in terms of human suffering is immeasurable. Currently there are no truly effective therapies, nor is there a cure. Most, if not all MS therapeutics produce serious side effects limiting their use. This is likely due to their non-specific interactions on non-MS targets. In contrast, antisense therapeutics are highly specific. Antisense therapeutics for MS can be developed as highly potent, non- toxic therapeutics, with little or no side effects.